Oxygen and glucose deprivation in autism and role of
calcium signalling

Neonatal hypoxia has been hypothesised to play an etiological
role in development of autism. In animal models, hypoxia and hypoxic
brain lesions are associated with some of autism-related neurobehavioral
symptoms, including withdrawal in social and novel situations,
diminished exploration in novel fields and repetitive behaviours
[14985924,
16482712,
8075818].

Both acute and chronic oxygen and glucose deprivation lead to
changes in membrane proteins, include excitation of chemoreceptors
as well as vasoconstriction and systemic vasodilatation (see Cerebral_Blood_Flow).
Hypoxia inhibits several potassium channels, leading to membrane
depolarization and excessive calcium entry through LTCC, and subsequent
downstream effects including release of calcium from intracellular
pools, contributing further to cytosolic calcium overload. These
events are thought to be G-protein linked [16828723].
Although a variety of membrane ion channels seem to be affected
by hypoxic conditions, LTCC seem to be most significantly affected
[14643931].

Neuronal damage during cerebral ischemia is thought to be mediated
mainly through increases in intracellular calcium. The activation
of LTCC and subsequently ryanodine-sensitive intracellular stores
during oxygen and glucose deprivation plays a major role in these
effects, which can be reduced in vitro by several calcium blocking
agents [9445351,
10826535].
In addition, in several animal studies application of nimodipine
resulted in prevention or reduction of adverse behavioural and
neurochemical effects of perinatal hypoxia. In one study it was
observed that nimodipine also enhanced the early postnatal development
of calcium-binding proteins [8817697],
while another study showed that alongside reducing negative behavioural
consequences, nimodipine reduced adrenal dysfunction and
abnormal corticosterone stress response in rats [8075818]
(see Hormones). A study looking at energy metabolism in the developing
brain damaged by aglycemic hypoxia found that calcium influx through
LTCC mediated these effects. Application of diltiazem or verapamil
but not nifedipine significantly improved the recovery from aglycemic
hypoxia, manifested in decreased ATP energy state
and increases in lactate [8897472]
(see Mitochondria). Nimodipine
and verapamil normalized cerebral pH following middle cerebral
artery occlusion in another roden model of ischemia [3793803].
It has been suggested that the dual blockade of calcium entry
using MK-801, a NMDA antagonist, alongside nimodipine may be a
useful tool for protection against ischemic brain damage in clinical
practice [1985301].

Upregulation of expression of several chemokine receptors
of CNS and their activation has been observed following perinatal
hypoxia and ischemia in animal models [16516309,
15467356]
and absence of the chemokine receptor CCR2 protects mice against
cerebral ischemia/reperfusion injury [17332467].
Both neuronal and glial cells possess a variety of chemokine receptors
that can regulate calcium and other signaling pathways - in normal
cirucumstances chemokine modulation of calcium homeostasis is
believed to have positive effects on neuronal development, but
excessive activation and expression of these receptors could have
long term effects on their function and gene expression, as well
as raise cellular vulnerability to viral and other proteins that
act as chemokine receptor agonists (see Viruses).
One of the pathways activated by chemokines is the calcium-mediated
CREB (see Brain) [11958818].

It is worth noting in this context that hypoxia is thought to
have a negative effect on the immune system –
in addition to its modulating effects on various genes related
to immune and inflammatory function observed in vitro [16849508],
in vivo studies have further confirmed these findings –
one example is the increased risk of infection by dysregulation
of Th1/Th2 cytokine balance and decrease in T lympocyte numbers,
as recorded in volunteers exposed to high altitudes [15870630].
On the other hand, the opposite mechanism has also been proposed,
whereas fetal exposure to infection (see Viruses)
and pro-inflammatory cytokines may reduce the threshold at which
hypoxia becomes neurotoxic, and so make the brain more vulnerable
to hypoxic insults [15707712].

It has been proposed that impairments of motor coordination
following hypoxia might be the result of altered function of Purkinje
neurons [16169666]
(see Brain and Motor/Sensory).
Perinatal anoxia has been observed to have negative effect on
development and functioning of auditory systems, also closely
linked to LTCC function [16365292]
(see Auditory).

Periods of prolonged hypoxia are associated clinically with an
increased incidence of dementia and raised suceptibility to development
of neurological disorders like Alzheimer’s disease. It has
been suggested recently that hypoxic channel up-regulation is
dependent upon formation of amyloid beta peptides,
which induce excessive activation of LTCC [16464656,
16321794,
12392105].
Blocking calcium channels by several antagonists has been shown
to be neuroprotective in models of Alzheimer’s disease (see
Related Disorders).

Amongst other types of cells the effect of hypoxia-induced dysregulations
in calcium traffic through voltage gated channels in arteries
may be of most relevance. A study looking at effect of hypoxia
on lateral artery in striatum, a subcortical area of the brain,
found substential gender difference in its vulnerability
to hypoxia. Chemically induced hypoxia in rats lead to calcium
overload and cell death, lesions, edema and immune activation.
These effects and subsequent motor disurbances were highly sex-dependent
and modulated by changes in hormonal levels, with males being
much more susceptible than females (see Gender_Differences)
[9678634].

In gastrointestinal tract, mucosal hypoxia is
closely associated with chronic inflammation, and these events
are dependent on alterations in the expression and function of
CREB, whose phosphorylation is in great part regulated by calcium
flux through LTCC [15253703]
(see Gastrointestinal and Brain).

Lastly, LTCC are thought to mediate hypoxia-induced vasoconstrictive
responses in human placenta, which could be completely abolished
by a relatively low doses of nifedipine [16368136].